Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent investigations indicate that telomerase activity regulates the life span of cells by compensating for telomere shortening during DNA replication. In addition, as differentiation progresses, telomerase activity is reduced in several different cell lineages. These findings lend support to the theory that more immature cells have greater remaining proliferative capacity and longer life span. However, it has not been directly demonstrated that the differentiation along a hepatocytic or a bile ductal lineage is accompanied by reduction of telomerase activity. In this study, we present direct evidence that telomerase activity is reduced during hepatocytic and biliary epithelial differentiation by using our unique cell lines including a stem-like cell line, ETK-1. When hepatocytic differentiation was induced in ETK-1 by 5-azacytidine, telomerase activity decreased significantly. Similarly, when we compared the telomerase activity on SSP-25 and RBE cell lines from the same origin but representing different maturation stages of cholangiocarcinoma, more mature cells were found to possess significantly lower activity. These results indicate that the generally accepted relationship between telomerase activity and differentiation stage also applies in the hepatocytic and biliary epithelial lineages.
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PMID:Telomerase activity is repressed during differentiation along the hepatocytic and biliary epithelial lineages: verification on immortal cell lines from the same origin. 1122 73

The effect of thiamine (vitamin B(1)) or riboflavin (vitamin B(2)) availability on fasting total homocysteine (tHcy) plasma levels in end-stage renal disease patients is unknown. A cross-sectional study was performed in a population of non-vitamin supplemented patients maintained on continuous ambulatory peritoneal dialysis. Red blood cell availability of thiamine (alpha-ETK) and of riboflavin (alpha-EGR), along with other predictors of tHcy plasma levels, was considered in the analysis. There was a linear association of alpha-EGR with tHcy plasma concentrations (P = 0.009), which was not observed for alpha-ETK. Among red blood cell vitamins, alpha-EGR was the only predictor of tHcy levels (P = 0.035), whereas alpha-ETK, red blood cell pyridoxal-5-phosphate supply (alpha-EGOT) and red blood cell folate levels had no effect. The risk for having a high tHcy plasma levels within the fourth quartile (plasma tHcy >38.3 micromol/L) was increased by an alpha-EGR > median (odds ratio, 4.706; 95% confidence interval, 1.124 to 19.704; P = 0.026). By way of contrast, alpha-ETK had no effect in these analyses. Independent predictors of tHcy plasma levels were serum albumin, alpha-EGR, red blood cell folate, and certain MTHFR genotypes. A logistic regression analysis showed that the MTHFR genotype is a predictor for having a tHcy plasma concentration within the fourth quartile. In summary, riboflavin availability, as measured by alpha-EGR, is a determinant of fasting tHcy plasma levels in peritoneal dialysis patients. This finding may have implications for tHcy lowering therapy in individuals with end-stage renal disease.
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PMID:Riboflavin is a determinant of total homocysteine plasma concentrations in end-stage renal disease patients. 1196 Oct 21

To investigate mechanisms predisposing to alcoholic brain damage, thiamine (vitamin B1 ), riboflavin (vitamin B2 ) and pyridoxine (vitamin B6 ) status was compared in persistent alcohol misusers (PAM) admitted for detoxification without evidence of significant brain damage, in alcoholics known to have severe chronic brain damage (BDAM), and in age, gender and ethnicity matched controls. Thus, activities of thiamine-dependent transketolase (ETK), riboflavin-dependent glutathione reductase, and pyridoxine-dependent aspartate amino transferase were assayed, together with the enzyme activities following addition of the appropriate co-factor. Twenty per cent of the PAM group had an abnormally low ETK activity and an abnormally high activation ratio, while 45% were abnormal in either one or both parameters. An additional 10% of the PAM group had an abnormally high activation ratio but normal ETK activity, as did 30% of the BDAM group. These subgroups of alcohol misusers may have increased requirements for thiamine secondary to an abnormality of the transketolase protein that may predispose such patients to alcoholic brain damage. There was no evidence of riboflavin or pyridoxine deficiency in either of the patient groups. We conclude that thiamine deficiency was commonly present in the alcoholic patients, and that a subgroup of patients may be predisposed to more severe brain damage as a consequence of abnormalities in the transketolase protein.
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PMID:Individual susceptibility to Wernicke-Korsakoff syndrome and alcoholism-induced cognitive deficit: impaired thiamine utilization found in alcoholics and alcohol abusers. 1245 26

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.
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PMID:The PPARgamma ligand, 15-Deoxy-Delta12,14-PGJ2, regulates apoptosis-related protein expression in cholangio cell carcinoma cells. 1461 59

AG 879 has been widely used as a Tyr kinase inhibitor specific for ErbB2 and FLK-1, a VEGF receptor. The IC(50) for both ErbB2 and FLK-1 is around 1 microM. AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice. In this paper we demonstrate that AG 879 even at 10 nM blocks the specific interaction between the Tyr-kinase ETK and PAK1 (a CDC42/ Rac-dependent Ser/Thr kinase) in cell culture. This interaction is essential for both the RAS-induced PAK1 activation and transformation of NIH 3T3 fibroblasts. However, AG 879 at 10 nM does not inhibit either the purified ETK or PAK1 directly in vitro, suggesting that this drug blocks the ETK-PAK1 pathway by targeting a highly sensitive kinase upstream of ETK. Although the Tyr-kinases Src and FAK are known to activate ETK directly, Src is insensitive to AG 879, and FAK is inhibited by 100 nM AG 879, but not by 10 nM AG879. The structure-function relationship analysis of AG 879 derivatives has revealed that both thio and tert-butyl groups of AG 879, but not (thio) amide group, are essential for its biological function (blocking the ETK-PAK1 pathway), suggesting that through the (thio) amide group, AG 879 can be covalently linked to agarose beads to form a bioactive affinity ligand useful for identifying the primary target of this drug.
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PMID:The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. 1473 83

Some field tests in counter-terrorism efforts to detect explosive traces employ chemistries that yield colored products. We have examined a test kit of this kind, ETK(Plus), based on widely used chemistries and employed extensively by the Israel Police. Our investigation focuses on the prospect of gaining sensitivity by replacing the normal colorimetric modality with photoluminescence detection, which, to our knowledge, has not been explored to date. We find two or more orders of magnitude sensitivity gains for all explosives studied, using field-worthy photoluminescence techniques. We have also investigated a general lanthanide-based photoluminescence approach which shows promise and the ability to photoluminescence-detect trace explosives in the presence of intense background color and/or background fluorescence by time-resolved imaging.
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PMID:Trace explosives detection by photoluminescence. 1500 19

Thiamin deficiency remains an important public health problem in some populations. The aim of the present investigation was to study thiamin status during the third trimester of pregnancy and its influence on the concentration of this vitamin in transition (days 13-14 of lactation) and mature breast milk (day 40 of lactation) in a group of Spanish women. The pregnancies and lactation periods of fifty-one healthy women 18-35 (mean 26.7 (SD 3.7)) years old were monitored. Vitamin intake during the third trimester was determined by recording the consumption of foods over 5 d and of the quantities provided by dietary supplements. Thiamin status during this stage of pregnancy was determined by measuring the activation coefficient of erythrocyte transketolase (alpha-ETK). Milk thiamin content was estimated (in 41% of the subjects) by oxidizing thiamin to thiocrome and measuring fluorescence. Subjects with thiamin intakes above that recommended (group H) had more satisfactory serum alpha-ETK coefficients (1.01 (SD 0.19)) than did those with lower intakes (group L) (1.21 (SD 0.30); P<0.05). Mature milk thiamin concentrations were significantly higher in group H subjects (0.59 (SD 0.44) micromol/l) than group L subjects (0.25 (SD 0.07) micromol/l). Subjects with alpha-ETK coefficients >1.25 in the third trimester had significantly lower mature milk thiamin concentration (0.31 (SD 0.10) micromol/l) than did subjects with more satisfactory alpha-ETK levels at this time (0.55 (SD 0.42) micromol/l; P<0.05). The thiamin status of women can be improved since 25.5% of subjects took less than that recommended and 13.7% showed signs of severe deficiency (alpha-ETK >1.25). The influence of maternal thiamin intake on alpha-ETK coefficients and on mature breast milk thiamin concentration is confirmed.
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PMID:Thiamin status during the third trimester of pregnancy and its influence on thiamin concentrations in transition and mature breast milk. 1523 Sep 96

To disclose molecular mechanisms of cholangiocarcinogenesis and to search for novel diagnostic markers and therapeutic targets for cholangiocarcinoma, we previously analyzed gene-expression profiles of 25 intrahepatic cholangiocarcinomas (ICCs) by means of a cDNA microarray re-presenting 27,648 genes. Among the genes frequently up-regulated in the cancer cells, we focused on PSF2 (partner of SLD five 2), a component of the GINS multiprotein complex that plays a crucial role in initiation of DNA replication. Semi-quantitative RT-PCR analysis of clinical samples confirmed high levels of PSF2 expression in the cancer cells, but expression of this gene was barely detectable in normal vital organs. Transfection of ETK-1 and HuH28 cells with short-interfering RNA specific to PSF2 reduced the amount of transcript and suppressed cell growth, suggesting that PSF2 may play an important role in development of cholangio-carcinoma. The findings reported here provide new insights into human cholangiocarcinogenesis and may contribute to the development of novel therapeutic drugs for this type of liver cancer.
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PMID:Up-regulation of PSF2, a member of the GINS multiprotein complex, in intrahepatic cholangiocarcinoma. 1607 78

The gal3 mutation is an insertion of a DNA sequence in the operator-promoter region of the galactose operon of E. coli. It reverts spontaneously to produce three kinds of gal+ revertants, which are: (i) stable and inducible, (ii) stable and constitutive, and (iii) unstable and constitutive. The constitutive revertants also show drastically reduced frequencies of transduction with lambda. The mechanism by which these reversions occur has remained unknown. It is proposed that the stable and inducible revertants arise by accurate excision of the insertion sequence. The unstable and constitutive revertants arise by tandem duplications of the gal operon in such a way that the structural genes of the extra copy of gal operon become connected to a different promoter. The resulting tandem configuration (gal3 ETK...P'E'T'K') permits constitutive expression and gal3 segregation (by internal recombination) simultaneously. The proposal was tested by comparison of the buoyant densities in CsCl of derivatives of a lambdagal phage carrying gal+, gal3, and the inducible and constitutive revertants. The densities of the inducible revertants were identical to the wild type, and the slight increase in density found to be associated with the gal3 insertion was missing. It was concluded that inducible revertants arise by excision of the inserted sequence. In contrast, lysates of a constitutive revertant exhibited several anomalous properties. The lysates contained a small quantity of phage whose density was identical to lambdagal3, produced few gal+ transductants (10(-3)-10(-4) of a normal HFT lysate), and the transductants were stable and constitutive. In turn, these abnormal transductants produced lysates which showed no lambdagal particles on centrifugation, and no transducing activity whatsoever. These anomalous properties of the constitutive revertant were attributed to the failure of lambda to package the DNA duplication efficiently. Transduction experiments with P1 (which can package more DNA than lambda) show that the unstable, constitutive reversions were located adjacent to prophage lambda. Segregation of the gal and lambda markers among the gal+ transductants was in accordance with the pattern expected for a duplication. Introduction of a recA marker resulted in stabilization of the reversion without affecting its constitutive expression. It was concluded that the unstable, constitutive reversion was a tandem duplication. It is further proposed that the stable, constitutive class of revertants might represent inverted (gal3 ETK...K'T'E'P') or partial tandem (gal3 ET...E'T'K') duplications of the gal operon.
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PMID:Mechanism of reversion of the gal3 mutation of Escherichia coli. 1609 75

Deregulation of the non-receptor tyrosine kinase ETK/BMX has been reported in several solid tumors. In this report, we demonstrated that ETK expression is progressively increased during bladder cancer progression. We found that down-regulation of ETK in bladder cancer cells attenuated STAT3 and AKT activity whereas exogenous overexpression of ETK had opposite effects, suggesting that deregulation of ETK may attribute to the elevated activity of STAT3 and AKT frequently detected in bladder cancer. The survival, migration and invasion of bladder cancer cells were significantly compromised when ETK expression was knocked down by a specific shRNA. In addition, we showed that ETK localizes to mitochondria in bladder cancer cells through interacting with Bcl-XL and regulating ROS production and drug sensitivity. Therefore, ETK may play an important role in regulating survival, migration and invasion by modulating multiple signaling pathways in bladder cancer cells. Immunohistochemistry analysis on tissue microarrays containing 619 human bladder tissue samples shows that ETK is significantly upregulated during bladder cancer development and progression and ETK expression level predicts the survival rate of patients with cystectomy. Taken together, our results suggest that ETK may potentially serve as a new drug target for bladder cancer treatment as well as a biomarker which could be used to identify patients with higher mortality risk, who may be benefited from therapeutics targeting ETK activity.
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PMID:Tyrosine kinase ETK/BMX is up-regulated in bladder cancer and predicts poor prognosis in patients with cystectomy. 2140 90


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